Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. coli and Targets Cell-Wall Synthesis

被引:75
作者
Antonoplis, Alexandra [1 ]
Zang, Xiaoyu [1 ]
Wegner, Tristan [2 ]
Wender, Paul A. [1 ,3 ]
Cegelski, Lynette [1 ]
机构
[1] Stanford Univ, Dept Chem, Stanford, CA 94305 USA
[2] Westfalische Wilhelms Univ Miinster, Organ Chem Inst, D-48149 Munster, Germany
[3] Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
OUTER-MEMBRANE; INTRINSIC RESISTANCE; ESCHERICHIA-COLI; TAT PROTEIN; ANTIBIOTICS; MECHANISM;
D O I
10.1021/acschembio.9b00565
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The emergence of multi-drug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae, is a major health problem that necessitates the development of new antibiotics. Vancomycin inhibits cell-wall synthesis in Gram-positive bacteria but is generally ineffective against Gram-negative bacteria and is unable to penetrate the outer membrane barrier. In an effort to determine whether vancomycin and other antibiotics effective against Gram-positive bacteria could, through modification, be rendered effective against Gram-negative bacteria, we discovered that the covalent attachment of a single arginine to vancomycin yielded conjugates with order-of-magnitude improvements in activity against Gram-negative bacteria, including pathogenic E. coli. The vancomycin-arginine conjugate (V-R) exhibited efficacy against actively growing bacteria, induced the loss of rod cellular morphology, and resulted in the intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disruption as its mechanism of action. Membrane permeabilization studies demonstrated an enhanced outer membrane permeability of V-R as compared with vancomycin. The conjugate exhibited no mammalian cell toxicity or hemolytic activity in MTT and hemolysis assays. Our study introduces a new vancomycin derivative effective against Gram-negative bacteria and underscores the broader potential of generating new antibiotics through combined mode-of-action and synthesis-informed design studies.
引用
收藏
页码:2065 / 2070
页数:6
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